Titanium-oxide clusters (TOCs) are well-defined molecular models for TiO2 materials and provide the opportunity to study the structure-activity relationships of TiO2. Here, we report a new Pb-doped TOC, Ti12Pb2, which resembles a two-layer decker of the {TiTi6} structural units of rutile TiO2 with two Ti4+ ions replaced by two Pb2+ ions. Its electronic structure, photoresponse, and photocatalytic performances were investigated and compared with those of the Ti14 cluster, which is isostructural to Ti12Pb2. Our results indicate that Pb2+ does not affect the electronic structure, but it greatly enhances the photocatalytic activity by improving the charge-separation and interfacial charge-transfer properties of the TOC. The successful synthesis of Ti12Pb2 highlights the roles of closed-shell heterometal ions in the construction of new TOCs. Our mechanism may be an inspiration for understanding the structure-activity relationships of closed-shell heterometal-doped TiO2.